Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma

肺癌是美国和全世界癌症死亡的主要原因，超过85%的 非小细胞肺癌(NSCLC)3例。我们计划的目标是推进临床前 非小细胞肺癌治疗学。在目前的资助期内，我们的计划有先进的抑制剂 EGFR，促进奥西美替尼和相关分子、TBK1和DDR2的临床前开发。在……里面 在接下来的5年里，我们的计划旨在开发能够导致更有效的治疗癌症的化合物 NSCLC并防止或克服对现有和未来靶向治疗的耐药性。 为实现这些目标，本方案力求通过3个相互关联和 协作项目和4个智力驱动的共享资源核心。 --总体目标1.开发针对突变的EGFR、KRAS信号效应器的抑制剂和/或降解剂，以及 非小细胞肺癌的转录适应机制。 --总体目标2.使用基因定义的方法对这些化合物及其靶标进行药理学表征 肺癌的细胞和动物模型。 --总体目标3.开发和评估这些有效和选择性的新药与现有药物的组合 预防和克服治疗阻力的治疗。 这些目标充分利用了化学和结构生物学方面的创新--变构激酶的发展 抑制剂和选择性降解剂-再加上肺癌生物学、肺癌细胞和 动物建模和功能基因组学方法，通过项目和 核心。这些广泛的目标将通过三个重点项目来实现，这些项目旨在开发关键的 非小细胞肺癌中的通路以及主要的耐药机制： --项目1：开发降低突变的EGFR的药理策略。 --项目2：确定KRAS驱动的肺癌的联合疗法。 --项目3：针对非小细胞肺癌治疗耐药的转录机制。 每个项目和整个计划都以创新、技术驱动的核心为基础，每个核心都由 在特定领域拥有专业知识的教师。 核心A：药物化学。 核心B：结构和生物化学。 核心C：动物建模和临床前治疗。 核心D：项目管理。 三个项目和四个核心的整合将使有效的协调能够满足 该计划旨在通过交叉受精肺癌的重点和技术专长。

Lung cancer is the leading cause of cancer death in the United States and world-wide, with over 85% of cases due to non-small cell lung cancer (NSCLC). The goal of our Program is to advance the pre-clinical science of NSCLC therapeutics. During the current funding period, our Program has advanced inhibitors of EGFR, promoting the pre-clinical development of osimertinib and related molecules, of TBK1, and of DDR2. In its next 5 years, our Program aims to develop compounds that will lead to more effective treatments for NSCLC and prevent or overcome resistance to existing and future targeted therapies. To accomplish these goals, the Program seeks to achieve the following overall aims via 3 inter-related and collaborative Projects and 4 intellectually driven Shared Resource Cores. --Overall Aim 1. Develop inhibitors and/or degraders focused on mutant EGFR, KRAS signaling effectors, and mechanisms of transcriptional adaptation in non-small cell lung cancer. --Overall Aim 2. Characterize these compounds and their targets pharmacologically using genetically defined cellular and animal models of lung cancer. --Overall Aim 3. Develop and assess combinations of these potent and selective novel agents with existing therapies to prevent and overcome therapeutic resistance. These aims leverage innovations in chemistry and structural biology—the development of allosteric kinase inhibitors and selective degraders—coupled with expertise in lung cancer biology, lung cancer cellular and animal modeling, and functional genomic approaches to understanding pathways, through the Projects and Cores. The broad aims will be implemented with three focused projects aimed at developing inhibitors of key pathways in NSCLC as well as over-arching mechanisms of resistance: --Project 1: Development of pharmacologic strategies to degrade mutant EGFR. --Project 2: Identification of combination therapy for KRAS-driven lung cancers. --Project 3: Targeting transcriptional mechanisms of therapeutic resistance in non-small cell lung cancer. Each Project and the overall Program is based on the innovative, technology-driven Cores, each led by faculty with expertise in the specific areas. Core A: Medicinal Chemistry. Core B: Structure and Biochemistry. Core C: Animal Modeling and Preclinical Therapeutics. Core D: Program Administration. The integration of the three Projects and the four Cores will enable an effective co-ordination to meet Program aims by cross-fertilization of lung cancer focus and technological expertise.